The spectrum of carcinoid tumours and carcinoid syndromes

The spectrum of carcinoid tumours and carcinoid syndromesCornelis JM Lips1, Eef GWM Lentjes2 and Jo WM Hoppener1
Addresses Departments of 1Clinical Endocrinology 2Laboratory Endocrinology University Medical Center Utrecht POB 85500, 3508 GA Utrecht The Netherlands
Correspondence Prof. dr CJM Lips E-mail: [email protected]
This article was prepared at the invitation of the Clinical Sciences Review Committee of the Association of Clinical Biochemists.
Abstract
Carcinoids are neuroendocrine tumours of the gut which may also be found in the bronchus, pancreatic islets and retroperitoneum. They probably arise from gastrointestinal or bronchopulmonary pluripotential stem cells. Carcinoid tumours derived from these cells are potentially malignant; the strength of the tendency for aggressive growth correlates with the site of origin, depth of local penetration and the size of the tumour. Carcinoids occur sporadically or result from speci c hereditary tumour syndromes. Mutations and/or aberrant expression of speci c genes induce and promote tumour growth. Clinical features include local symptoms due to angulation or obstruction and hepatomegaly due to liver metastases.
The carcinoid syndrome commonly involves ushing, diarrhoea, bronchospasm and hypotension. Other distinct syndromes may be caused by tumour release of products that may also be used as biochemical markers in diagnosis and follow-up. Scanning using radiolabelled octreotide, an analogue of somatostatin, sensitively identies occult primary and metastatic deposits.
Localized carcinoid tumours should be resected. Some patients bene t from hepatic resection. Palliation of symptoms is best achieved with octreotide. Hepatic artery chemoembolization may produce long-acting palliation.
Further genetic characterization of the different types and stages of carcinoid development as well as assessment of gene expression pro les may improve differential diagnosis, prognosis and treatment.
Ann Clin Biochem 2003; 40: 612–627
Introduction
De nition of carcinoid tumours Carcinoids are neuroendocrine tumours that usually arise from enterochroma¤n (EC) cells, which are found scattered throughout the body but occur prin- cipally in the submucosa of the intestine and main bronchi (Kulchitskycells). Many types of tumour, such as bronchial carcinomas, gastric and pancreatic endocrine tumours, form part of a spectrum of carci- noid tumours. Carcinoid is a collective term for tumours with common histological, cytochemical and ultrastructural characteristics. They share the expression pattern of a neuroendocrine phenotype and may produce and contain amines, polypeptides and/or prostaglandins. The carcinoid syndrome is caused by systemic release of one or more of these products. The clinical picture depends on the pro¢le of the released products.
Originally, carcinoid was a term used by patholo- gists; it was later adopted by all clinicians, but in future the term may become increasingly inap- propriate to designate the full range of neuro- endocrine neoplasms of low and intermediate malignant potential. Biological markers re£ecting the speci¢c pro¢les of gene expression will allow more precise classi¢cation of these tumours, which is needed if treatment is to be e¡ective for improved life -expectancy and quality of life.
History In 1888, Lubarsch described the clinical and histolo- gical picture of carcinoid tumours.1 Oberndorfer, who introduced the word `Karzinoid’, wrote in 1907: `they resemble carcinoma histologically, but have a more benign clinical course of the disease’.2 In 1914, Gosset and Masson3 discovered the argenta¤n properties of carcinoid cells and their origin in the crypts of LieberkÏhn. They named them `argenta¤nomas’.
612 © 2003 The Association of Clinical Biochemists
Review Article
Lembeck4 isolated serotonin from carcinoid tumours. Thorson et al. identi¢ed the carcinoid syndrome for the ¢rst time in a patient with metastases of an intest- inal carcinoid to the liver.5 Sandler and Snow reported6 an `atypical’ carcinoid tumour of the stomach with di¡erent staining properties and a di¡erent type of £ush (bright red rather than cyanotic or livid). In 1969, Pearse7 described the common cytochemical characteristics and ultrastructural features (presence of neurosecretory granules) of EC cells and formulated the APUD (amine content, precursor uptake and decarboxylation) concept in the di¡use neuroendocrine system.
Classi cation Williams and Sandler8 classi¢ed carcinoid tumours according to their embryological origin (foregut, midgut or endgut), staining characteristics (histo- chemistry) and clinical behaviour (seeTable1). Foregut carcinoids are able to reduce silver salts to a black metallic silver stain only after prior treatment with a reducing agent and are called `argyrophilic’. Midgut carcinoids stain with silver salts without pre-treat- ment with a reducing agent, because serotonin itself has su¤cient reducing capacity, and are referred to as `argenta¤n’. Endgut carcinoids do not show any reac- tion with silver.
Incidence and prevalence In consecutive post-mortem investigations, carcinoids in the small intestine were found in about one of 150 individuals.9 In addition, they were detected in the appendix in approximately one of 300 append- ectomies.10 They may be discovered incidentally during proctoscopy (one per 2500). The overall inci- dence of clinically manifest carcinoid tumours in the USA has been estimated to be one to two cases per
100 000 inhabitants.11,12 A Swedish study, in which the frequency of carcinoid was calculated on the basis of both surgical specimens and autopsies in a single geographic location, reported the incidence to be 8.4 cases per 100 000 people.13 A Swedish nation-wide database revealed an incidence of 2.0/100 000 for men (main site: small intestine) and 2.4 for women (main site: appendix).14 On the basis of all these data, one may conclude that carcinoid tumours occur rela- tively frequently but are only rarely manifest. There is a higher risk of developing a carcinoid tumour among ¢rst-degree relatives of patients with a carcinoid tumour. These patients may also have an increased risk for other malignancies (see later). Alternatively, according to a study in the Mayo Clinic, familial predisposition to carcinoid may occur without co- occurrence of other tumour types.15
Tumour location (distribution and frequency of carcinoid tumours) A review by Modlin and Sandor of the National Cancer Data Registry found that out of 8305 carcinoid tumours studied 74% were located in the gut and 25% in the pulmonary system (see Table 2).12 These authors compared their data from 1973-1991 with those of Godwin11 from 1950-1971 and concluded that inci- dence had increased in the last10 years; theyattributed this to improved diagnostic techniques, including widespread use of endoscopy, ultrasonography, com- puterized axial tomography (CT) and somatostatin scintigraphy. In addition, the increased recognition of di¡erent clinical manifestations had changed surgical indications and criteria for registration.
Pathology Carcinoid tumours of the gastrointestinal tract are generally slow-growing, but are sometimes aggressive.
The spectrum of carcinoid tumours and carcinoid syndromes 613
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Table 1. Classi cation of carcinoid tumours
Origin Product and histochemistry Carcinoid syndrome Metastases to bone
Foregut Thymus 5-Hydroxytryptophan Sometimes (atypical) + Bronchus Argentaf n7(Masson) Stomach Argyrophil+(Grimelius) Duodenum Pancreas
Midgut Jejunum Serotonin Often (after metastasizing to the liver) Rare Ileum Argentaf n+ve Colon ascendens Argyrophil+ve
Endgut Transverse colon Argentaf n7ve Rare + Distal colon Argyrophil7ve Rectum
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There is a good correlation between tumour size and metastatic spread. Tumours less than1cm in diameter rarely metastasize, whereas tumours larger than 2 cm almost always metastasize to regional lymph nodes and liver.
Di¡erenthistological forms occur: insular, trabecular, glandular, undi¡erentiated, or mixed.16 Grimelius and Masson silver staining is based on the reducing capa- city (H+ donation) of the tumour. Grimelius silver staining is positive if 5-hydroxytryptophan is present. The argenta¤n reaction (Masson) is positive if 5- hydroxytryptamine (serotonin) is present. Frequently, there is a positive histological reaction with poly- peptides such as chromogranin A, synaptophysin, neuron-speci¢c enolase, cytokeratin and S100 protein. The mitotic index, based on Ki-67 staining, gives an indication of the degree of malignancy of the tumour.
Products of carcinoid tumours
Biosynthesis of serotonin Tryptophan is the precursor of serotonin and an essential amino acid (see Fig. 1). Under normal circumstances, only1% is transformed into serotonin, and more than 90% is available for the synthesis of protein and niacin (vitamin B7). Niacin is the essential
Ann Clin Biochem 2003; 40: 612–627
Table 2. Tumour location and associated frequency of carcinoid tumours
Location Frequency (%)
Jejunum, ileum 26 Tracheobronchopulmonary 25 Appendix 19 Rectum 13 Colon 8 Stomach 3 Pancreatic islet 3 Duodenum 2 Others* 1
Data taken from the literature (inter alia Reference 12). *Oesophagus, ovary, testis, prostate, kidney, breast, skin, etc.
Figure 1. Biosynthesis and degradation of serotonin (5-hydroxytryptamine). Serotonin is produced in the argentafn cells of the midgut from the essential amino acid tryptophan by the classical APUD (amine content, precursor uptake and decarboxylation) enzymes hydroxylase and decarboxylase. Serotonin is degraded in the liver and kidney by the enzymes monoamine-oxidase and aldehyde-dehydrogenase, respectively. Normally, 51% of available tryptophan is converted into serotonin. However, if extensive metastatic disease is present, this percentage is much higher and pellagra may develop if no nicotinamide is administered. 5-HIAA ˆ 5-hydroxyindoleacetic acid.
The spectrum of carcinoid tumours and carcinoid syndromes 615
component of nicotinamide (vitamin B3) and for the formation of NAD and NADP, the co-enzymes and H+
carriers in tissue metabolism, glycolysis and lipid synthesis.
Shortage of tryptophan due to excessive conversion to serotonin in carcinoid tumours may cause nicotin- amide de¢ciency. In addition, patients may develop pellagra (i.e. diarrhoea and dementia) as well as hypoproteinaemia and protein malnutrition.
Large amounts of serotonin may be produced by intestinal (midgut) carcinoids. Consistently higher concentrations, notably in platelets, were observed in 96%, 43% and 0% of patients with mid-, fore- and endgut carcinoids, respectively.17 Serotonin is meta- bolized in the liver by the enzyme monoamine oxidase and only low concentrations of serotonin are normally present in the systemic circulation; however, in the presence of carcinoid metastases in the liver, much serotonin escapes degradation by the liver and will act on the heart and lungs, having a mitogenic e¡ect on smooth muscles, causing vasoconstriction, broncho- constriction and platelet aggregation and resulting in pulmonary hypertension and endocardial ¢brosis.
Noradrenaline Many carcinoids produce noradrenaline. Urinary noradrenaline/adrenaline metabolites, notably nor- metadrenaline and metadrenaline, were increased in 33%, 20% and 14% of patients with mid-, hind- and foregut carcinoids, respectively. The content of cate- cholamines, which enhance serotonin production and release, in carcinoid tumours is independent of the primary location.17 The catecholamine noradrenaline produced by intestinal carcinoids is degraded by monoamine oxidase and catechol-O-methyltransferase in the liver.
Other products, other syndromes Many other products (amines, polypeptides and pros- taglandins) can be released by carcinoid tumours and may cause distinct syndromes (see Box 1). Examples of carcinoid-related syndromes include Zollinger- Ellison syndrome (ZES), Cushing’s syndrome, the syndrome of watery diarrhoea, hypokalaemia and achlorhydria, and the glucagonoma syndrome.
Genetics Association of carcinoid with genetic syndromes Carcinoids occur sporadically, or in the context of an hereditary tumour syndrome. Three di¡erent genetic syndromes appear to be associated with the develop- ment of carcinoid tumours. The gene mutated in each of these syndromes has been identi¢ed. Each of these genes functions as a tumour suppressor gene and the corresponding syndromes are caused by loss of
function of the gene. Due to this genetic predisposition for tumour formation, as a consequence of a germline mutation in all cells of the body, carcinoids are often multicentric in familial patients, as opposed to solitary carcinoids in a non-familial (sporadic) context. In up to 40% of patients with a non-familial, sporadic carcinoid tumour studied, a somatic inactivating mutation is present in the same gene that causes the corresponding hereditary tumour syndrome.18
The three familial syndromes are:
1. Multiple endocrine neoplasia syndrome type 1 (MEN1). Patients with MEN1 develop parathyroid hyperplasia or adenoma in approximately 95% of the cases. About two-thirds of MEN 1 patients develop pancreatic endocrine tumours (PETs), which are mostly non-functional or produce gastrin or insulin. On pathological criteria, PETs in MEN1 patients may be classi¢ed as carcinoid tumours of the foregut. Carcinoid tumours of the
Ann Clin Biochem 2003; 40: 612–627
Amines Dopamine Histamine 5-Hydroxytryptophan Noradrenaline (norepinephrine) Serotonin (5-hydroxytryptamine)
Proteins Adrenocorticotrophin (ACTH) Bradykinins Calcitonin Chromogranins Corticotrophin releasing hormone b-Endorphin Gastrin Growth hormone releasing hormone (GHRH) Glucagon Growth hormone Insulin Islet amyloid polypeptide Kallikrein Neurokinin A Neurokinin B Neuropeptide K Neurotensin Pancreatic polypeptide Peptide YY Parathyroid hormone related peptide Somatostatin Substance P Vasoactive intestinal protein (VIP)
Prostaglandins PGE2 PGF2a
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thymus gland, stomach or bronchial tree are present in about one-third of patients. Pituitary adenomas are found in approximately 40%, adrenocortical tumours in approximately 20%. The MEN1 gene is located on the long arm of chromosome 11 (region 11q13). In MEN1 patients, carcinoids often exhibit loss of heterozygosity (LOH) at11q13, with deletion of the wild-type MEN1 gene allele, in accordance with the tumour suppressor nature of the MEN1gene product.
2. Von Hippel-Lindau disease (VHL). Patients with VHL develop haemangioblastomas in the cere- bellum (55%), myelum (15%) and retina (50%). In addition, renal cell carcinomas (30%) and phaeo- chromocytoma (10%) occur. In15% of VHL patients non-functional PETs are detected. A mutation in theVHL gene located on chromosome 3q25 is found in all patients.
3. Neuro¢bromatosis type 1 (NF-1), or von Reck- linghausen’s disease. In patients with NF-1, neuro- ¢broma and cafe au lait spots of the skin are combined with Lisch nodules in the iris. In a signi¢cant minority of patients, carcinoid of the duodenum (somatostatinomas) may occur. Muta- tions may be found in the NF-1 gene located on chromosome 17q11.
Incidentally, non-functional PETs may be found in patients with the tuberous sclerosis complex (TSC). Patients with TSC have small nodules (tubera) in the central nervous system and, rarely, angiomyolipomas of the kidneys. Two loci are indicated in the germline defect in TSC: TSC1 on chromosome 9 (q34) and TSC2 on chromosome 16 (p13.3). In a 12-year-old boy with TSC, LOH of the TSC2 gene was demonstrated in a malignant PET.19
Patients with familial carotid body paraganglioma appear to have no greater risk of developing carcinoid of the fore- mid- or endgut than normal individuals. However, their paraganglioma may be able to produce serotonin.20,21 The germline defect in familial para- ganglioma is on chromosome 11q (see next section).
Genes involved in foregut and midgut carcinoids Foregut carcinoid Carcinoids in MEN1 patients are mostly of foregut origin (thymus, lung, pancreatic islets, stomach, duodenum), whereas midgut and hindgut carcinoids usually do not occur in these patients. LOH at the MEN1 gene locus at chromosome 11q13 can be seen in most MEN1-associated carcinoids. For example, 11q13 LOH has been shown in 75% of MEN1-ZES carci- noids,22 in 85% of MEN1 PETs (non-gastrinomas) and in 41% of MEN1 gastrinomas.23
In sporadic carcinoid tumours 11q13 LOH may also be seen, indicating a similar mechanism of tumour
formation. D’Adda et al. found LOH at chromosome 11q13 in12 of 23 sporadic PETs.24 Similar results were reported by Zhuang et al.25 and by Debelenko et al.23
with LOH at 11q13 in 50% and 19% of sporadic insulinomas. LOH at 11q13 has also been demon- strated in 65% of carcinoids of the thymus gland, in 48% of sporadic carcinoids of the stomach (type 1, related to atrophic gastritis), in 36% of carcinoids of the lung18 and in 44% and 93% of sporadic gastri- nomas of the pancreas, the peripancreatic region or the wall of the duodenum.23,25 The consistent exten- sion of LOH from the MEN1region at11q13 to the distal end of the long arm of chromosome 11 (11qter) in sporadic PETs suggests chromosomal breakage and complete loss of chromosome 11q as the underlying mechanism in these foregut endocrine tumours. LOH distal to 11q13 has also been reported in sporadic carcinoid tumours of the lung26 and in MEN1 tumours.27 These data suggest involvement of an addi- tional speci¢c tumour suppressor gene, located more distally to11q13 (e.g. the SDHD gene; see next section).
An association between X-chromosome deletions and malignancy was found among 17 PETs (foregut endocrine tumours), but not among 17 midgut or hindgut carcinoids, suggesting that di¡erent mol- ecular mechanisms are involved in the tumorigenesis of these two categories of endocrine neoplasms.28
Although the underlying mechanism is unclear, it is notable that thymic carcinoids occur only in male patients (who have only one X chromosome per cell).
Midgut carcinoids Several chromosomal regions and genes have been implicated in the pathogenesis of midgut carcinoids. The tumour suppressor gene encoding succinate- ubiquinone oxidoreductase subunit D (SDHD) is constitutionally mutated in familial paragangliomas of the head and neck, and is located on the distal part of 11q (i.e. telomeric from the MEN1 gene on 11q13). KytÎlÌ et al.29 detected LOH at the SDHD gene locus in ¢ve of eight informative midgut carcinoids. In two of these ¢ve midgut carcinoids, a missense mutation in the SDHD gene itself was demonstrated, in association with LOH of the other allele, which suggests that alterations of the SDHD gene might be involved in the tumorigenesis of midgut carcinoids. As patients with familial paragangliomas have no increased risk of carcinoids of the gut, mutations in the SDHD gene are not likely to act as primary events initiating carcinoid tumorigenesis.
In an earlier study30 of 18 midgut carcinoids, employing comparative genomic hybridization, KytÎlÌ et al. demonstrated numerical chromosomal imbal- ances in 16 of the 18. The most common aberrations were losses of18q22-qter (in two-thirds) and of11q22- q23 (in one-third). Losses of 18q and 11q were present
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The spectrum of carcinoid tumours and carcinoid syndromes 617
both in the primary tumours and in metastases, indi- cating that such deletions represent early events in the tumorigenesis of midgut carcinoids.
In another study of eight classical midgut carci- noids, genome-wide screening for LOH revealed deletions on chromosome 18 in seven of them.31 These data strongly suggest that involvement of a putative tumour-suppressor gene telomeric from 18q22 is a frequent and early event speci¢cally in the development of midgut carcinoids.
To summarize, foregut carcinoids are often asso- ciated with the MEN1 gene on 11q13. In mid- and endgut carcinoids, no LOH was found in this region. Similarly, an association between X-chromosome deletions and malignancy has been demonstrated32
for foregut carcinoids (gastric carcinoids type 1 and PETs), but not for midgut carcinoids. In midgut carci- noids, LOH has been frequently observed at the SDHD gene (distal 11q) and distal 18q.
Additional molecular events Cellular accumulation of the b-catenin protein and mutations in the b-catenin gene on 3p21indicate that deregulation of the Wnt signal transduction pathway is a common event among gastrointestinal carci- noids.33 There has been no indication of genomic instability, i.e. defective DNA mismatch repair, which is found in several other types of tumours.34 Neither have associations been found between carcinoids and p53 or Rb, two tumour suppressor genes commonly mutated in carcinomas.35,36
Further genetic characterization of the di¡erent types and stages of carcinoid development as well as assessment of gene expression pro¢les (messenger RNA and protein) using microarray technologies may improve di¡erential diagnosis, prognosis and treatment.
Clinical presentation Symptoms and signs of the carcinoid syndrome The carcinoid syndrome is mediated by humoral factors produced by carcinoid tumours (see Box1). The most common manifestations are vasomotor changes (£ushing), gastrointestinal hypermotility (diarrhoea), bronchospasm (wheezing, dyspnoea) and hypotension.
The carcinoid syndrome associated with gastro- intestinal carcinoids develops in 510% of such patients and requires the presence of metastases to the liver. The explanation for this phenomenon is the hepatic inactivation of tumour products released into the portal circulation. Bronchial and ovarian carci- noids secrete their products directly into the main bloodstream and are associated with carcinoid syndrome in the absence of liver metastases. Major symptoms are £ushing and tachycardia (90%),
diarrhoea, hypotension and sweating (75%).37 Hista- mine, bradykinin, tachykinins and prostaglandins may cause asthmatic symptoms. Long-term e¡ects include pulmonary hypertension, endocardial and valve ¢brosis, which may result in cardiac insu¤- ciency (30%).38 In addition, high concentrations of serotonin may cause retroperitoneal or mesenteric ¢brosis and arthritis.
Flushing and diarrhoea Flushing Depending on location and stage of the tumour, four di¡erent types of £ushing may be distinguished.39
Type 1 £ushing is seen in an early stage of midgut carcinoid that has metastasized to the liver, lasting 1-5 min and is di¡use and erythematous.…